The present invention relates generally to antibiotic mitosane compounds and to their use in the treatment of neoplastic disease states in animals.
Pertinent to the background of the invention are those antibiotics which are isolated from the fermented broth of Streptomyces verticillatus and named Mitomycin A, B, and C. The structures of these three compounds are well known in the art [being eludicated, for example, in a publication of J. S. Webb, et al., in J.A.C.S., 84, 3185 (1962)] and are set out below. ##STR5##
Mitomycin A, B, and C are acknowledged as excellent antibiotics but are relatively highly toxic to humans. This has prompted the prior art synthesis of numerous mitomycin derivatives and analogs in an attempt to secure compounds having equal or enhanced antibiotic activity but lesser toxicity than the naturally-occuring mitomycins. Among the mitomycin derivatives having structures and activities of interest to the present invention are those described in U.S. Letters Pat. Nos. 3,332,944 (Colusich, et al.); 3,450,705 (Matsui, et al.); and 3,514,452 (Matsui, et al.), as well as in Kinoshita, et al., J. Med. Chem., 14, No. 2, 103-112 (1971) and French Pat. No. 1,449,947.
Also of interest of the present invention are reports of workers in the art that certain mitomycins and mitomycin derivatives possess a degree of in vivo antitumor activity. See, e.g., Oboshi, et al., GANN, 58, 315-321 (1967); Usubuchi, et al., GANN, 58 307-313 (1967); Matsui, et al., J. Antibiotics, XXI, No. 3, 189-198 (1968); Japanese Pat. No. 68 06,627 to Matsui, et al. [as reported in Chem. Abstracts, Vol. 69, 86986K (1968)] and Cheng, et al., J. Med. Chem., 20, No. 6, 767-770 (1977). The last-mentioned publication by the inventor and one of his co-workers discloses activity against P388 leukemia in mice for mitomycin A, mitomycin C and N-methylmitomycin A.
Mitomycin C is assertedly active against a relatively broad spectrum of experimental tumors including both hematological and solid types. In clinical practice, however, its use is limited to certain carcinomas owing to its toxicity and particularly its myelosuppressive effects. See, e.g., "Mitomycin C: Current Status and Developments", Carter, et al. Eds., Academic Press, New York (1977). Numerous analogs of mitomycin C have been prepared in the hope of obtaining compounds with improved therapeutica properties, especially antitumor properties. The semi-synthetic analogs of the above-noted patents and publications have involved substituents on the aziridine ring, carbamoyl or acyl groups on the hydroxymethyl side chain, and replacement of the 7-substituent in the quinone ring with other functional groups, especially substituted amines. None of these analogs has emerged as a clinical agent, although a 7-hydroxy analog of mitomycin C has received intensive study recently in Japan. This analog is asserted to be less leukopenic than mitomycin C, although it is also much less potent. Totally synthetic mitomycin analogs of the mitosene [Mott, et al., J. Med. Chem., 21, 493 (1978)] and indoloquinone [Weiss, et al., J. Med. Chem., 11, 742 (1968)] types have been prepared, but mainly for their antibacterial activity. The most active antitumor agent of the mitosene type is considerably less active than mitomycin C.
The art, therefore, persists in its search for new and useful compounds which are structurally related to the mitomycins, which possess antibiotic activity, have low toxicity and display a substantial degree of antitumor activity in animals.